How TPO-RA Drugs Fared in Meta-Analyses of Safety and Efficacy in ITP Patients

Introduction

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by a complex pathophysiology − increased destruction of platelets and impaired production. It often appears without a discernible cause. People with a significant drop in platelets then have an increased tendency to bleed.

The traditional approach to ITP treatment includes glucocorticoids, high-dose immunoglobulins, immunomodulatory drugs including rituximab, and splenectomy. All these approaches primarily aim to influence immune-mediated platelet destruction. In many patients, these strategies have some effect, but many are refractory to the treatment. Additionally, some suffer from its side effects.

TPO-RA in the Treatment of ITP

Thrombopoietin receptor agonists (TPO-RA) are TPO mimetics that bind to the TPO receptor and activate it, promoting the maturation, proliferation, and differentiation of megakaryocytes, leading to increased platelet production. Both romiplostim and eltrombopag, and more recently avatrombopag, from the TPO-RA group have been studied in numerous randomized controlled trials, both in adults and children. The results of these studies are very encouraging, and TPO-RAs are often used in treatment already as a second-line option, relatively early after the diagnosis of ITP.

The following two systematic reviews with meta-analyses evaluated the safety and efficacy of TPO-RAs in patients with primary ITP.

Meta-analysis #1

The 2016 analysis included 13 randomized controlled trials (RCTs) with pooled results clearly showing that these drugs lead to a significant increase in platelet response (relative risk [RR] 2.77; 95% confidence interval [CI] 2.01−3.82) and a sustained response (RR 7.52; 95% CI 3.94−14.35).

Concurrently, TPO-RA administration led to a significant reduction in the incidence of any bleeding (RR 0.80; 95% CI 0.67−0.95) and severe bleeding (RR 0.52; 95% CI 0.27−0.99).

The results further suggest a significant decrease in the proportion of patients treated with TPO-RAs needing rescue medication, compared to the control group.

Meta-analysis #2

The 2021 meta-analysis included studies of avatrombopag and other studies released up to December 2018. It determined the relative risk (RR) of treatment failure and WHO grade 2 and higher bleeding, as well as the rate of remission after discontinuation of TPO-RAs. The primary target safety parameter was the risk incidence of thrombotic events and liver damage.

The meta-analysis included 16 randomized controlled trials and 19 cohort studies. A total of 909 patients received TPO-RAs, and 427 were in the RCT control group. Treatment failure was observed in 21% of patients treated with TPO-RAs and 47% in the control group (RR 0.42; 95% CI 0.33−0.53) with a median follow-up of 13 weeks. Furthermore, 29% of patients treated with TPO-RAs in cohort studies experienced treatment failure with a median follow-up of 69 weeks. The incidence of remission after discontinuation of TPO-RAs was 18%, RR of observed bleeding was 0.58 in patients treated with TPO-RAs compared to the control group. There were no significant differences in adverse events between the observed groups. All-cause mortality was significantly lower in patients treated with TPO-RAs (RR 0.21; 95% CI 0.06−0.68).

Conclusion

Both cited meta-analyses generally demonstrated the safety and efficacy of TPO-RAs in treating primary ITP, even in long-term follow-ups.

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Sources:
1. Wang L., Gao Z., Chen X. et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: a systematic review and meta-analysis. SciRep 2016; 6: 39003, doi: 10.1038/srep39003.
2. Birocchi S., Podda G. M., Manzoni M. et al. Thrombopoietin receptor agonists for the treatment of primary immune thrombocytopenia: a meta-analysis and systematic review. Platelets 2021 Feb 17; 32 (2): 216−226, doi: 10.1080/09537104.2020.1745168.